Reproductive Disease Flashcards
Hormonal Control of Male Reproduction
The hypothalamus-pituitary-gonad (HPG) axis is essential for both male and female reproduction
- Releases GnRH which transports to the pituitary to stimulate the secretion of FSH and LH
- FSH binds to FSH receptors in Sertoli cells and stimulate the production of anti-mullerian hormone (AMH during fetal life stage), inhibin, activin, estradiol
- LH binds to LH receptors in Leydig cells and stimulate the production of androgen (testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA)
Where do FSH bind and what does it stimulate?
FSH bind to the FSH receptor in the Sertoli cell
- Stimulate the production of antimullerian hormones (Inhibin, activin, estradiol)
Where do LH bind and what does it stimulate?
LH bind to the LH receptor in Leydig cells
- Stimulate the production of androgens ( (testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA))
Cryptorchidism
Male Reproductive disease
Phase I: The testis decends into the lower abdomen (AMH dependent; uncommon 5-10%)
Phase II: The testis decend into the scrotum via the inguinal canal (androgen dependent; 90%)
- A complete or a partial failure of the intra-abdominal testes to descend into the scrotum
- 1-3% of 1 year old boys (spontaneous desent occurs within a year); bilateral in 25% and unilateral in 75% of all patients
Cryptorchidism
Clinical Consequences
- Testicular dysfunction
- Infertility
- Increased risk of testicular cancer
What is Phase I of Cryptorchidism and what is it dependent on?
Testis descend into lower abdomen
- AMH dependent
What is Phase II of Cryptorchidism and what is it dependent on?
Testies descend into the scrotum via inguinal canal
- Androgen dependent
Cryptorchidism
Pathology change
Pathological change occur as early as two years of age
- Thick basement membrane
- Loss of spermatogonia with Sertoli cells only
Cryptorchidism is a marker of?
Similar pathological changes may be seen in contralateral testis; indicating that Cryptorchidism is a marker of defective gonad development
Testicular Tumors
Classification:
- Germ cell tumor (GCTs; common 95%)
–Seminomatous (primordial germ cell-like cells)
– Non-seminomatous tumor (embryonic stem cell-like cells)
- Sex cord stromal tumor
Not as common as Cryptorchidism
- Rare worldwide (1.5/100000), higest in Caucasian males and lowest in Africa/Asia
Testicular Tumor
Factors: GTC
Associated with both environmental and genetic factors
- Environmental Factors: Gestational exposure to pesticides and non-steroid estrogens (endocrine disruptors, EDCs)
- Genetic Factors: Variant in receptor tyrosine kinase KIT and BAK
Uterus
- Where an embryo implants, resides, and develops
- Three layers with histological and structural changes during
menstrual cycle in response to ovarian sex hormones
HPG hormonal regulation and Uterus
Look at screenshots
Pregnancy
Ovulation => Fertilization (day 1) => Cell division takes place (Days 2-4) => Blastocyst reaches uterus (day 4-5) => Implantation (day 5-9)
Premature Ovarian Insufficiency/Failure
POI/POF
Amenorrhea or menopause before 40 years of age with <1000 priordial follices
- Associated post menopause syndrome: endocrine disorders, and infertility, and systemic defects (e.g. bone loss)
- Lab results: Low estrogen, High FSH, Low AMH, and absence of LH surge
- Caused by genetic mutation, cancer treatment, environmental exposure
Fragile X Syndrome
POI/POF
Mutation of the FMR1 genes (X chromosome)
- Cause abnormal brain development
- Intellectual disabilities
- POI
- Associated with reproductive dysfunctions
Doxorubicin drug
POI/POF
Preserve fertility before chemo
Polycystic Ovarian Syndrome (PCOS)
- 10-15% incidence in adolescent and reproductive aged women
- Symptoms: hyperandrogenism, anovulation, polycystic ovary (infertility, irregular period, obesity, diabetes …)
Hyperplasia of theca cells (androgen producer) => produce more androgen
PCOS Etiology
- Unknown
- Defective HPG control
- Genetic mechanisms
- Environmental exposure (gestational exposure to high androgen)
RH => Stimulate theca cells => Androgen production
Ovarian Tumor
Classifications
Based on Malignance
- Benign ovarian tumor (20-45 years old 80%)
- Borderline ovarian tumor (slightly older age)
- Malignant ovarian tumor or cancer (post-menopausal age)
Based on Origin
- Ovarian surface/fallopian tube epithelium or endometriosis (most common)
- Germ cell ovarian tumor, which migrate to the ovary from yolk sac and are pluripoten (abnormal PGC)
- Stromal/sex cord cell ovarian tumors
Most common Ovarian Tumor
Based on malignance:
- Benign ovarian tumor (80%, 20 - 45 years of age)
Based on origin:
- Ovarian surface/fallopian tube epithelium or endometriosis
(most common)
Ovarian Tumors
80% are benign and 20% are cancerous;
- Benign ovarian tumor can be asymptomatic
- Ovarian cancer accounts for 3% of all cancers in women but is the 5th most common cause of death (deadliest)
Symptoms of ovarian cancer:
- Abdominal pain,
- Urinary and GI tract symptoms,
- Vaginal bleeding
Ovarian Tumors
Type I & II
Type I: Benign to borderline ovarian tumor (Endometrioid, Mucinous)
- Low grade serous ovarain cancer has KRAS and BRAF mutation
Type II: High-grade serious ovarian cancer (e.g. STIC)
- Pathogenesis: Ovulation induced inflammation, Germline mutation of BRCA1, BRCA2 or TP53 tumor suppressor genes
Endometriosis
The presence of endometrial tissue (glad+stroma) outside the uterus
- 10% in reproductive women (most common in 30s - 40s)
Clinical Consequences:
- Infertility
- Dysmenorrhea
- Painful menstruation
- Pelvic pain
Endometriosis
Payhpgenesis and treatment
Three pathogenesis theories:
1) from uterine endometrium – retrograde menstruation or via blood vessels;
2) transformation of peritoneal cells;
3) from stem or progenitor cells
- Going to cause a release of proinflammatory and angiogenic factors
Treatments:
- Hormones (aromatase inhibitor),
- Surgery,
- Pain killer
Endometrial Hyperplasia
Abnormal proliferation of the endometrial glads relative to stroma
Symptoms:
- Irregular period,
- Heavy bleeding
- Anemia
Treatment:
- Progesterone therapy,
- Hysterectomy
Endometrial Hyperplasia and Neoplasia
Pathogenesis
Pathogenesis: prolonged and unopposed estrogen stimulation:
- Obesity
- PCOS
- Anovulation
- Granulosa cell tumor
- Estrogenic substance exposure
- Mutation of tumor suppressor gene PTEN (20%)
Endometrial Neoplasia
Types: Endometrioid Carcinoma (adenocarcinoma, 80%) and serous endometrial carcinoma
Symptoms:
- Bleeding between periods
- Vaginal bleeding after menopause
- Pelvic pain
Treatment: Chemo, radiation, hormone therapy, immunotherapy, hysterectomy …
Endometrial Neoplasia
Type I
Age: 55-65 years
Clinical Setting: Unopposed estrogen, Obesity, Hypertension, Diabetes
Morphology: Endometrioid
Precursor: Hyperplasia
Mutated genes: PTEN, FGF2, MSI, POLE,….
Behavior: Indolent, Spread via lumphatics
Endometrial Neoplasia
Type I
Adenocarcinoma: PIO or high estrogen
1) Well differentiated (grade 1) with preserved grandular architecture and lack of intervening stroma
2) Moderately differentiated (grade 2) with grandular architecture but mixed with solid areas
3) Poorly differentiated (grade 3) with a predominantly solid growth pattern
Endometrial Neoplasia
Type II
Age: 65-75 years
Clinical Setting: Atrophy, thin physique
Morphology: Serous, Clear cell, Mixed mullerian tumor
Precursor: Serous endometrial intraepithelial carcinoma
Mutated genes: TP53, Aneuplody, CCNE1, PIK3CA,…
Behavior: Aggressive, Intraperitoneal and lymphatic spread
Endometrial Neoplasia
Type II
Serous endometrial carcinoma: p53
1) Early stage of type II endometrial intraepithelial carcinoma, the precursor to serous carcinoma
2) Strong, diffuse expression of altered p53 in endometrial intraepithelial carcinoma.
3) Serous endometrial carcinoma with papillary growth pattern consisting of malignant cells with marked cytologic atypia including high nuclear-to-
cytoplasmic ratio, atypical mitotic figures, and hyperchromasia.
4) Accumulation of altered p53 protein
